Structure and molecular function of the DREAM complex in gene expression programs of cellular quiescence.

The cell cycle is the fundamental biological process where the cell coordinates chromosome replication and segregation with cell growth and division. In response to internal/external cues individual metazoan cells exit from the cell cycle. Cell cycle exit is reversible during cellular quiescence, a process crucial for tissue regeneration and cancer cell resistance to therapy. Progression through the cell cycle is promoted by the cyclins, which activate the cyclin-dependent kinases. During quiescence, cyclin gene expression is repressed by the DREAM complex, which assembles at cyclin gene promoters, thereby repressing their transcription. To understand the DREAM complex molecular function in quiescence, I propose to reconstitute and determine the cryo-electron microscopy structures of the ~450 kDa 8-subunit human DREAM protein complex, the complex of DREAM with its target DNA sequences and the nucleosome, and to perform structure-based functional studies in biochemical assays and cancer cell lines. The DREAM complex pathway is misregulated in ovarian carcinoma, where it promotes the formation of quiescent tumour cells resistant to therapy. Understanding the molecular mechanism of DREAM-mediated cell cycle regulation will allow to (i) understand the molecular biology of quiescence and to (ii) design novel anticancer drugs to be used in more effective therapies against ovarian cancer.